Antitumor activity of a PKC-alpha antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted into nude mice.
A 20-mer phosphorothioate oligodeoxynucleotide (ODN) directed against human protein kinase C-alpha (CGP 64128A = ISIS 3521) was analyzed for its antitumor activity either alone or in combination therapy. Combination studies with CGP 64128A and standard chemotherapeutic agents (cisplatin, mitomycin-C, vinblastine, estracyt and adriamycin) were performed in nude mice that had been transplanted s.c. with a variety of human tumors (breast, prostate, large cell lung and small cell lung carcinomas, and melanomas). Additive antitumor effects with CGP 64128A and the cytotoxins were found for half of the combinations studied. The combination of CGP 64128A with vinblastine or cisplatin showed superadditive antitumor activities against MCF-7 human breast carcinomas and PC3 prostate carcinomas with complete responses. CGP 64128A in combination with adriamycin resulted in superadditive antitumor effects against BT20 human breast carcinomas with complete tumor responses, and in combination with mitomycin-C superadditive antitumor effects with cures were observed against NCI-H460 human large cell carcinomas. The antitumor activity of CGP 64128A appeared to be due to a sequence-dependent mechanism of action as two 20-mer control ODNs were completely inactive as single agents against A549 and NCI-H69 human lung carcinomas. The antitumor activity of cisplatin against NCI-H69 human small cell lung carcinomas was slightly inhibited by one of the control ODNs, indicating that the superadditive antitumor activities of CGP 64128A in combination with cisplatin are the result of a sequence-dependent mechanism of action.
Geiger
T
T
Department of Oncology, Novartis Pharma Inc., Basel, Switzerland.
Müller
M
M
Dean
N M
NM
Fabbro
D
D
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000235:genetics*; D051571:Protein Kinase C-alpha; D013873:Thionucleotides / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007527:Isoenzymes; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; C108494:ISIS 3521; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha